The invention concerns the use of 5-(1,2-dithiolan-3-yl) valeric acid (xcex1-lipoic acid) or its physiologically compatible salts for the treatment of disturbances of lipid metabolism.
Arteriosclerosis, after heart disease and cancer, is one of the primary causes of death in humans. A risk factor for the disease of arteriosclerosis is an increased quantity of serum lipids and lipoproteins, so that a decrease in the level of serum lipids and lipoproteins is important for therapy.
An object of the present invention is thus to make available an active ingredient, which is suitable for the treatment of disturbances of lipid metabolism.
The present invention comprises treating disorders or disturbances in lipid metabolism using 5-(1,2-dithiolan-3-yl) valeric acid (xcex1-lipoic acid) or its physiologically compatible salts. The invention comprises administering to a subject afflicted or thought to be afflicted with a lipid metabolic disorder an effective amount of 5-(1,2-dithiolan-3-yl) valeric acid or a physiologically acceptable salt thereof.
In another aspect, the present invention comprises using 5-(1,2-dithiolan-3-yl) valeric acid (xcex1-lipoic acid) or a physiologically acceptable salt thereof for the production of pharmaceuticals for the treatment of lipid metabolic disorders.
Lipid metabolic disorders which can be treated using the compositions of the invention include, for example, hyperlipidemia and/or hyperlipoproteinemia, particularly hypercholesterolemia and/or hypertriglyceridemia.
It has been found surprisingly that xcex1-lipoic acid is effective for the treatment of disturbances of lipid metabolism. Administration of xcex1-lipoic acid leads to a significant reduction in the blood lipid values both in persons having normal blood lipid values, as well as those having dyslipoproteinemias. These results are independent of whether a simultaneous hypertonia is being treated with medication.
xcex1-Lipoic acid was isolated for the first time by Reed et al. (Science, 114, p. 93 (1951) and has been used since 1961 as a pharmaceutical for diabetic polyneuropathy and polyneuritis. The production of xcex1-lipoic acid is known in and of itself and is described, for example, in U.S. Pat. No. 2,980,716 and U.S. Pat. No. 3,049,549.xcex1-Lipoic acid has been used for the treatment of polyneuropathy, preferably of diabetic polyneuropathy, in doses of approximately 600 mg/day. The compatibility of oral and parenteral therapy at these doses is very good. In accordance with the present invention, the effective doses for the treatment of disturbances of lipid metabolism are within the same order of magnitude and are thus equally well compatible.
In the present invention, free xcex1-lipoic acid, or a physiologically compatible salt thereof can be used for treatment of a lipid metabolic disorder. Suitable salts can be prepared in ways known in and of themselves from xcex1-lipoic acid with the addition of bases. Suitable bases include, for example, metal hydroxides, particularly alkali and alkaline-earth hydroxides and organic acids, such as, for example, ethylenediamine, trometamol and methylglucamine.
The salts can be obtained by known methods of making pharmaceutical salts, such as, for example, by mixing a free base or a solution thereof with xcex1-lipoic acid or a solution thereof in an organic solvent. Suitable organic solvents include, for example, a lower alcohol such as methanol, ethanol, n-propanol or isopropanol or a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether, such as diethyl ether, tetrahydrofuran, or dioxane. For better separation of the crystals, mixtures of the solvents may also be used. The salts of xcex1-lipoic acid also may be prepared by well-known ion exchange methods.
The subject of the present invention also includes pharmaceuticals for oral, rectal, subcutaneous, intravenous or intramuscular application, which contain xcex1-lipoic acid or its physiologically compatible salts as an active ingredient, in addition to the usual carrier and dilution agents.
The pharmaceuticals of the invention are prepared in the known way with the usual solid or liquid carrier substances or dilution agents and the commonly used technical pharmaceutical adjuvants corresponding to the desired type of application with a suitable dosage. The preferred preparations comprise a form of administration, which is suitable for oral application. Such forms of administration are, for example, tablets, film tablets, sugar-coated pills, capsules, pills, powders, solutions or suspensions or repository forms.
Of course, parenteral preparations, such as injection solutions, are also considered. Further, suppositories will also be named, for example, as forms of preparation.
Corresponding tablets can be obtained, for example, by mixing the active ingredient with known adjuvants, for example, inert dilution agents, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, bursting agents such as corn starch or alginic acid, binding agents such as starches or gelatins, slip additives such as magnesium stearate or talcum and/or agents for obtaining a repository effect, such as carboxy polymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also be comprised of several layers.
Appropriately, sugar-coated pills can be prepared by coating analogous cores prepared from tablets with means used commonly in the coating of sugar-coated pills, for example, polyvinylpyrrolidone or shellac, gum Arabic, talcum, titanium dioxide or sugar. Thus, the envelopes for the sugar-coated pills can also comprise several layers, whereby the above-mentioned adjuvants for tablets can be used.
Solvents or suspensions containing the active ingredient according to the invention can also contain agents that improve the taste, such as saccharin, cyclamate or sugar, as well as, for example, flavoring substances such as vanilla or orange extract. They may also contain adjuvants for effecting suspension such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients may be prepared, for example, by mixing the active ingredient with an inert carrier such as lactose or sorbitol and encapsulating in gelatin capsules.
Suitable suppositories can be produced, for example, by mixing with the carrier agents provided for this purpose such as neutral fats or polyethylene glycol or its derivatives.
The following example explains the invention: